It has recently emerged that the classical fast neurotransmitters glutamate and GABA could under some conditions escape the immediate synaptic cleft exerting remote actions at neighbouring synapses. By manipulating the function of NMDA receptors in a use-dependent manner we have shown that cross-talk between synapses could represent up to 20-30% of high-affinity glutamate signalling in the hippocampus. To monitor the extent of this extrasynaptic communication, we have developed a methodology that probes extracellular diffusivity at high-resolution using two-photon photobleaching. We also combined fast multi-photon microscopy with path-clamp electrophysiology to monitor neural activity together with evoked Ca 2+ signalling at individual synapses in the hippocampal circuitry. We find that presynaptic activity at single synapses of one modality (e.g., glutamatergic) can be controlled by local receptors of another modality (e.g., GABA receptors). These results identify mechanisms that underlie the physiological significance of extrasynaptic neurotransmitter spillover.

What would these extrasynaptic neurotransmitter actions imply for information transfer in the brain? Will the "dilution" of point connections decrease the network storage capacity? How is this compatible with the Hebbian learning rules? In fact, experimental evidence emerges suggesting that non-Hebbian mechanisms of synaptic modification are required for the neural networks to perform their tasks efficiently. Furthermore, recent findings propose that diffuse signalling arising from multiple glutamate releases in the hippocampus could selectively facilitate induction of long-term depression (LTD) of synaptic links; in contrast, synaptic releases tend to trigger long-term potentiation (LTP) at the immediate, releasing synapse. We argue that Hebbian LTP at point connections combined with non-Hebbian LTD via glutamate spillover might contribute to the optimization of memory storage in the hippocampal network.